Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials)

Background

Statin therapy has been associated with the development of type 2 DM, particularly in patients with higher blood pressures, elevated fasting plasma glucose (FPG) and higher triglyceride (TG) concentrations [1]. These parameters are also associated with insulin resistance, an independent predictor of T2DM [2,3].
It is hypothesised that the identification of insulin-resistant individuals before the initiation of statin treatment would decrease the risk of developing statin-related T2DM. Insulin resistance is increased in patients with prediabetes mellitus (PreDM), which is defined by an FPG concentration of ≥5.6 mmol/l (100 mg/dl) and <7.0 mmol/L (126 mg/dl) [4,5].
In this study, the impact of combining a diagnosis of PreDM with a measurement of either fasting TG concentration >1.7 mmol/l (>150 mg/dl) or a BMI of ≥27.0 kg/m2 on the identification of individuals on high risk of statin-associated T2DM was evaluated. 939 incident cases (8.2%) of T2DM were identified during a median follow-up of 4.9 years, in a study population pooled from patients without DM in the Treating to New Targets (TNT) and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials.

In patients with PreDM, there was a substantially increased baseline risk for incident T2DM even with placebo treatment. Incident T2DM occurred in 7.6% of placebo treated patients with PreDM and TG ≤ 1.7 mmol/l, and 17.9% of placebo treated patients with PreDM and TG >1.7 mmol/l.

Statin treatment significantly increased the risk of T2DM in patients with PreDM compared to placebo: 22.8% of PreDM patients and TG >1.7 mmol/l developed incident T2DM, a 27% increased risk versus those on placebo.

HR for developing T2DM on statin treatment was significantly higher (p <0.001) in patients with either a TG concentration of >1.7 mmol/L (1.5; 95% CI: 1.2-2.0), or PreDM 4.0; 95% CI: 3.3-4.9, or both (6.7; 95% CI: 5.4-8.2), compared to those with NFG and TG ≤ 1.7 mmol/l.

Similar results were seen for the combination of PreDM and BMI, with HR for patients with NFG and BMI ≥ 27 kg/m2: 1.4; 95% CI: 1.1-1.9, HR for patients with PreDM and BMI <27 kg/m2: 3.5; 95% CI: 2.7-4.5, HR for patients with PreDM and BMI ≥27 kg/m2: 7.0; 95% CI: 5.6-8.6.

Conclusion

These data suggest that the statin-related incidence of T2DM is quite modest, but is aggravated if plasma glucose, TG concentrations and BMI increase. The authors have created a simple 4-tier category system, based on PreDM, TG concentrations and BMI, which may be helpful in identifying individuals at high risk of developing statin-associated T2DM.